Systemic insulin resistance induces cognitive and psychiatric symptoms in Alzheimer's disease model mice

[Speaker] Naotaka Izuo:1
[Co-author] Nobuhiro Watanabe:2, Yoshihiro Noda:3, Takashi Saito:4, Takaomi Saido:4, Harumi Hotta:2, Takahiko Shimizu:1
1:Department of Advanced Aging Medicine, Graduate School of Medicine, Chiba University, Japan, 2:Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Japan, 3:Animal Facility, Tokyo Metropolitan Institute of Gerontology, Japan, 4:Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Japan

[Introduction] Alzheimer's disease (AD) is a neurodegenerative disease, which exhibits cognitive and psychiatric symptoms. Amyloid (Abeta), a component of senile plaques, is one of causative proteins to AD. Recent epidemiological studies indicate that type 2 diabetes increase the risk of AD onset. Notably, a report from the Hisayama Study showed the increased risk of AD onset is associated with glucose intolerance, not with fasting blood glucose level (Ohara et al., Neurology 2011), suggesting that insulin resistance plays a key role in AD pathogenesis. In this study, we generated and analyzed the AD model mice with insulin resistance to investigate the impacts of insulin resistance on AD pathology. [Methods] For AD model mice, we selected mutant amyloid precursor protein (AppNL-G-F/NL-G-F) knockin mice (APP-KI), which were reported to overproduce human Abeta42 with arctic mutation and cognitive impairment from 6 months of age (Saito et al., Nat. Neurosci. 2014). APP-KI were crossbred with mutant insulin receptor (P1195L) knockin mice (mIR-KI) to obtain AD model mice with systemic insulin resistance (mIR, APP-KI). mIR-KI were reported to exhibit glucose intolerance and hyperinsulinemia despite normal fasting glucose level (Baba et al., J. Biol. Chem. 2005). We evaluated metabolic parameters at 3 months of age, and performed behavioral test at 4 months of age. [Results] First, we confirmed that mIR, APP-KI exhibit normal fasting glucose levels, impaired glucose tolerance and hyperinsulinemia. In the behavioral test, mIR, APP-KI showed global abnormalities, such as time extension staying in open arms in elevated plus maze test, decreased alternation in Y-maze test, and severed immobility in forced swimming test. In an immunohistochemical analysis, there is no acceleration of senile plaque deposition in mIR, APP-KI compared with APP-KI. [Discussion] These results suggest that systemic insulin resistance induces cognitive and psychiatric symptoms at a younger age, independent of senile plaque deposition.
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